Somatostatin (SRIF) is not only a major endocrine hormone and physiological inhibitor of growth hormone, glucagon, and insulin secretions but has a variety of other functions as well. SRIF analogs are used in the treatment of several pathological conditions by modulating or targeting one or more of the five known membrane-associated receptor subtypes (sst1-5). The actual function, distribution, and specificity of these different receptors and their mechanism of action are not fully understood due, in part, to the lack of potent and selective agonists and antagonists and inherent limitations of techniques presently available. Following up on existing leads and information derived from NMR spectroscopy, computer simulations, and binding and functional assays in vitro, we will design, synthesize, and characterize SRIF analogs with defined structures that have agonist and antagonist properties for the five receptor subtypes. Because of the critical role played by sst2 and sst5 in the inhibition of glucagon and insulin secretion, respectively, and their role in diabetes, we will emphasize the development of sst2-selective agonists and sst5-selective antagonists. Similarly, ligands to any or all SRIF receptors will be used for receptor-targeted scintigraphy and radionuclide therapy of certain cancers. Preliminary investigations demonstrate that such peptide analogs are accessible using both rational and limited combinatorial approaches. We will investigate the solution conformation of our lead constrained agonists and antagonists using spectroscopic and computational approaches to understand peptide/receptor interactions (structural studies). Using this information, we will identify structural motifs of both receptors and ligands and specific amino acids responsible for selective binding and transduction and design improved SRIF agonists and antagonists that could also be labeled (pharmacological studies). Using this approach, we have successfully designed potent and selective sst1 agonists and sst3-selective antagonists. Additionally, we have promising leads for the development of sst2- and sst5-selective ligands and of sst4-selective agonists using subtle conformational constraints found in beta-methylated amino acids and betidamino acids. We will identify the human targets of those analogs and investigate the usefulness of some selected SRIF analogs as potential drugs or tools to understand related pathophysiological states. Several investigators (10 letters attached) enthusiastically offered to collaborate in the biological (in vivo and in vitro) characterization of our sst-selective analogs demonstrating the significance of generating sst-selective ligands.